Japanese Patent No. 2591640 (Patent Document 1) discloses 17α-acetoxy-6-chloro-15β-hydroxy-2-oxapregna-4,6-diene-3,20-dione (15β-hydroxy-osaterone acetate) and discloses that this compound has an antiandrogenic activity and is effective as an agent for preventing, curing, and/or treating androgen-dependent diseases, for example, benign prostatic hyperplasia, prostatic cancer, alopecia, hypertrichosis, contusion, and seborrhea. The Patent Document 1 describes synthesis of 15β-hydroxy-osaterone acetate but does not describe crystals of 15β-hydroxy-osaterone acetate.
Chem. Pharm. Bull. 41(5) 870-875 (1993) (Nonpatent Document 1) relates to a process for producing the above-mentioned compound. This document discloses that a mixture of 15β,17α-diacetoxy-6-chloro-2-oxapregna-4,6-diene-3,20-dione, potassium carbonate, methanol, and water is stirred at a room temperature, water is added to the reaction mixture, the resulting product is extracted with ethyl acetate, the resulting organic phase is washed with water and is dried over anhydrous magnesium sulfate, solvents are removed from the resulting solution, and then the resulting crude product is purified by thin-layer chromatography (TLC) to give 15β-hydroxy-osaterone acetate (melting point (mp) 285 to 288° C. (acetone-hexane)).
These documents do not describe crystalline polymorphic forms (or crystalline polymorphs). However, when the above compound is prepared according to the methods described in these documents, a crystal of 15β-hydroxy-osaterone acetate (hereinafter, simply referred to as a crystalline form B) is obtained. Unfortunately, the resulting crystalline form B has an insufficient stability. For example, the crystal not only has a low storage stability (thermal stability) and decreases in purity with storage but also fails to maintain the crystal form by a pressure action such as pulverization or crushing and decreases in purity. Further, the crystal has a low powder flow property (flowability), and the crystal not only has a low handleability in blending operation for a preparation but also is hard to obtain a preparation having a constant active ingredient content due to a varying active ingredient content in a preparation. Furthermore, in pharmacokinetics, the crystalline form B has not only a high Cmax (maximum plasma concentration) of the active ingredient but also a short Tmax (time to reach Cmax). Accordingly, since the crystalline form B reaches Cmax within a short period of time and shows a rapid absorbability, the crystalline form B has a concern for safety.